Breast cancer response to cytotoxic drugs by analyzing markers of apoptosis and cell proliferation

Terapijski odgovor karcinoma dojke na delovanje citotoksičnih lekova se znatno razlikuje i samo će deo pacijentkinja odgovoriti na datu hemioterapiju usled pojave ili razvoja neosetljivosti tumora na primenjenu terapiju. Zbog toga je poželjno unapred znati verovatnoću odgovora tumora na terapiju koja se razmatra. Prediktivni marker se može definisati kao faktor koji ukazuje na osetljivost ili rezistenciju na određenu terapiju. Neoadjuvantni modalitet lečenja karcinoma dojke ili preoperativna (primarna) sistemska terapija predložena je kao optimalan in vivo model za istraživanje bioloških svojstava tumora koji mogu postati pouzdani markeri u proceni odgovora tumora na terapijui/ili značajni pokazatelji dugotrajnog toka bolesti. Osim toga, primena neoadjuvantne hemioterapije daje mogućnost provere kliničkog značaja obrasca izmene fenotipa ćelije koja je izazvana terapijom, pri čemu tumor ostaje in situ kao pouzdana in vivo mera terapijskog odgovora. Prediktivni markeri u okviru neoadjuvantnog modaliteta primene hemioterapije se procenjuju u odnosu na povezanost sa objektivnim odgovorom tumora, a na osnovu toga da je nastanak kompletne patološke regresije tumora dosledno povezan sa poboljšanim ishodom bolesti. To znači da se odgovor tumora procenjen na osnovu patoloških kriterijuma može smatrati pravim „surogat“ pokazateljem koji može pouzdano predvideti dejstvo terapije na krajnji klinički ishod. Proces proliferisanja i apoptoza razmatraju se kao najznačajniji in vivo fenomeni koji su povezani sa dejstvom hemioterapije na nivou ćelija. Zahvaljujući saznanjima da mnogi antitumorski agensi sa raznovrsnim mehanizmom delovanja ostvaruju citotoksičnost, bar delimično, izazivanjem apoptoze nemogućnost da se izvrši apoptotski program smatra se značajnim faktorom za pojavu rezistencije na citotoksične lekove. Sa obzirom na to da je sklonost određene ćelije ka apoptozi određena balansom između stimulatornih i inhibitornih faktora koji su ispoljeni u takvoj ćeliji, izmenjena ekspresija ili mutacija ključnih gena čiji proteinski produkti doprinose poremećenoj apoptozi može biti značajna za razvoj primarne i stečene rezistencije na citotoksične lekove. Brojni citotoksični stimulusi i prenosni signalni molekuli koji pobuđuju proces apoptoze, sustiču se na nivou mitohondrija da bi izazvali promenu propustljivosti spoljašnje mitohondrijalne membrane i na taj način su povezani sa različitim ćelijskim odgovorom...Breast cancers vary widely in their response to cytotoxic drugs and only a proportion of patients will respond to a particular chemotherapy, due to the emergence and development of tumor insensitivity to applied therapy. It is therefore desirable to know, in an advance, the likelihood of a tumor responding to the therapy under consideration. Predictive marker can be defined as a factor that indicates sensitivity or resistance to a specific treatment. Neoadjuvant clinical setting or preoperative (primary) systemic therapy of breast cancer has been proposed as an ideal in vivo model for studying the tumor biological features that might become reliable markers for the assessment of tumor response to therapy and/or valuable indices for long–term disease outcome. In addition, the use of neoadjuvant chemotherapy offers the opportunity to test clinical relevance of the pattern of modifications in the cell phenotype induced by therapy with the tumor remaining in situ throughout treatment as an in vivo measure of response. Predictive markers in the setting of neoadjuvant chemotherapy have been assessed in terms of correlation with objective tumor response, on the basis that the induction of pathological complete remission in particular, has been consistently found to be associated with improved disease outcome. This implys that pathological tumor response can be considered as a true surrogate indicator that can reliably predict the effect of a treatment on the final clinical outcome. The proliferation kinetics and apoptosis pathway are considered as the most relevant phenomena that are associated with cellular effects induced in vivo by chemotherapy. Owing to the knowledge that many anticancer agents with differing modes of action achieve cytotoxic effects, at least partly, by inducing apoptosis the impossibility of performing an apoptotic program is considered as an important factor in the appearance of resistance to cytotoxic drugs. Considering that the susceptibility to apoptosis of a given cell is determined by the balance between stimulatory and inhibitory factors manifested in a particular cell, altered expression or mutation of key genes whose protein products contribute to disturbed apoptosis may be relevant in development of intrinsic and acquired resistance to cytotoxic drugs. Numerous cytotoxic stimuli and proapoptotic signal transducing molecules converge on mitohondria to induce outer mitochondrial membrane permeabilization and thus are related to different cellular response..

Levels of estrogen receptor B splice variant (ERBΔ5) mRNA correlates with progesterone receptor in breast carcinomas

It is well known that breast tumors which are estrogen positive ER(+) are more likely to respond to hormone therapy. However, a certain percentage of ER(+)/PR(+) tumors do not respond to this therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ERβ), as well as the existence of numerous isoforms/splice variants of both ERα and ERβ, suggests that a complex regulation of estrogen action exists. In this study, we analyzed the expression ratio of ERβ1 isoform and ERβΔ5 splice variant mRNAs, and its correlation with ER/PR status by quantitative RT-PCR and clinical and histopathological parameters. We found that the relative proportion of ERβΔ5 in the total ERβ1 transcript 'pool' inversely correlates with the PR level (p = -0,359, p< 0,003, Spearman). It may be that the ERβΔ5 variant modulates the ERα activity of downstream targets. In addition, we suggest that the determination of the expression profiles of ERα and ERβ isoforms and splice variants in the defined groups of patients are necessary for elucidating their involvement in endocrine resistance

Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells (vol 7, 3763, 2017)

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Trefoil Factor 1 in Early Breast Carcinoma: A Potential Indicator of Clinical Outcome during the First 3 Years of Follow-Up

Background. A role of an estrogen-regulated, autocrine motogenic factor was assumed to be a major biological role of trefoil factor 1 (TFF1) in breast cancer. TFF1 is regarded as a predictive factor for positive response to endocrine therapy in breast cancer patients. The aim of our study was to examine TFF1 level distribution in breast carcinomas in order to distinguish estrogen-independent from estrogen-dependent TFF1 expression and to evaluate clinical usefulness of TFF1 status in early breast cancer during the first 3 years of follow-up. Methods. The study included 226 patients with primary operable invasive early breast carcinomas for whom an equal, a 3-year follow-up was conducted. TFF1 levels as well as estrogen receptor (ER) and progesterone receptor (PR) levels were measured in cytosolic extracts of tumor samples by immunoradiometric assay or by use of classical biochemical method, respectively. Non-parametric statistical tests were applied for data analyses. Results. Statistical analysis revealed that TFF1 levels were significantly higher in premenopausal patients (p=0.02), or in tumors with: lower histological grade (p LT 0.001), positive ER or PR status (p LT 0.001, in both cases). On the basis of TFF1 level distribution between ER-negative and ER-positive postmenopausal patients with tumors of different histological grade, 14 ng/mg was set as the cut-off value to distinguish estrogen-independent from estrogen-dependent TFF1 expression in breast cancer. Depending on menopausal and PR status, positive TFF1 status identified patients at opposite risk for relapse among ER-positive patients with grade II tumors. Among ER-and and PR-positive premenopausal patients with grade II tumors, TFF1 status alone identified patients at opposite risk for relapse. Conclusions. Determination of TFF1 status might identify patients at different risk for relapse and help in making decision on administering adjuvant therapy for early breast cancer patients during the first 3 years of follow-up

Breast cancer response to cytotoxic drugs by analyzing markers of apoptosis and cell proliferation

Terapijski odgovor karcinoma dojke na delovanje citotoksičnih lekova se znatno razlikuje i samo će deo pacijentkinja odgovoriti na datu hemioterapiju usled pojave ili razvoja neosetljivosti tumora na primenjenu terapiju. Zbog toga je poželjno unapred znati verovatnoću odgovora tumora na terapiju koja se razmatra. Prediktivni marker se može definisati kao faktor koji ukazuje na osetljivost ili rezistenciju na određenu terapiju. Neoadjuvantni modalitet lečenja karcinoma dojke ili preoperativna (primarna) sistemska terapija predložena je kao optimalan in vivo model za istraživanje bioloških svojstava tumora koji mogu postati pouzdani markeri u proceni odgovora tumora na terapijui/ili značajni pokazatelji dugotrajnog toka bolesti. Osim toga, primena neoadjuvantne hemioterapije daje mogućnost provere kliničkog značaja obrasca izmene fenotipa ćelije koja je izazvana terapijom, pri čemu tumor ostaje in situ kao pouzdana in vivo mera terapijskog odgovora. Prediktivni markeri u okviru neoadjuvantnog modaliteta primene hemioterapije se procenjuju u odnosu na povezanost sa objektivnim odgovorom tumora, a na osnovu toga da je nastanak kompletne patološke regresije tumora dosledno povezan sa poboljšanim ishodom bolesti. To znači da se odgovor tumora procenjen na osnovu patoloških kriterijuma može smatrati pravim „surogat“ pokazateljem koji može pouzdano predvideti dejstvo terapije na krajnji klinički ishod. Proces proliferisanja i apoptoza razmatraju se kao najznačajniji in vivo fenomeni koji su povezani sa dejstvom hemioterapije na nivou ćelija. Zahvaljujući saznanjima da mnogi antitumorski agensi sa raznovrsnim mehanizmom delovanja ostvaruju citotoksičnost, bar delimično, izazivanjem apoptoze nemogućnost da se izvrši apoptotski program smatra se značajnim faktorom za pojavu rezistencije na citotoksične lekove. Sa obzirom na to da je sklonost određene ćelije ka apoptozi određena balansom između stimulatornih i inhibitornih faktora koji su ispoljeni u takvoj ćeliji, izmenjena ekspresija ili mutacija ključnih gena čiji proteinski produkti doprinose poremećenoj apoptozi može biti značajna za razvoj primarne i stečene rezistencije na citotoksične lekove. Brojni citotoksični stimulusi i prenosni signalni molekuli koji pobuđuju proces apoptoze, sustiču se na nivou mitohondrija da bi izazvali promenu propustljivosti spoljašnje mitohondrijalne membrane i na taj način su povezani sa različitim ćelijskim odgovorom...Breast cancers vary widely in their response to cytotoxic drugs and only a proportion of patients will respond to a particular chemotherapy, due to the emergence and development of tumor insensitivity to applied therapy. It is therefore desirable to know, in an advance, the likelihood of a tumor responding to the therapy under consideration. Predictive marker can be defined as a factor that indicates sensitivity or resistance to a specific treatment. Neoadjuvant clinical setting or preoperative (primary) systemic therapy of breast cancer has been proposed as an ideal in vivo model for studying the tumor biological features that might become reliable markers for the assessment of tumor response to therapy and/or valuable indices for long–term disease outcome. In addition, the use of neoadjuvant chemotherapy offers the opportunity to test clinical relevance of the pattern of modifications in the cell phenotype induced by therapy with the tumor remaining in situ throughout treatment as an in vivo measure of response. Predictive markers in the setting of neoadjuvant chemotherapy have been assessed in terms of correlation with objective tumor response, on the basis that the induction of pathological complete remission in particular, has been consistently found to be associated with improved disease outcome. This implys that pathological tumor response can be considered as a true surrogate indicator that can reliably predict the effect of a treatment on the final clinical outcome. The proliferation kinetics and apoptosis pathway are considered as the most relevant phenomena that are associated with cellular effects induced in vivo by chemotherapy. Owing to the knowledge that many anticancer agents with differing modes of action achieve cytotoxic effects, at least partly, by inducing apoptosis the impossibility of performing an apoptotic program is considered as an important factor in the appearance of resistance to cytotoxic drugs. Considering that the susceptibility to apoptosis of a given cell is determined by the balance between stimulatory and inhibitory factors manifested in a particular cell, altered expression or mutation of key genes whose protein products contribute to disturbed apoptosis may be relevant in development of intrinsic and acquired resistance to cytotoxic drugs. Numerous cytotoxic stimuli and proapoptotic signal transducing molecules converge on mitohondria to induce outer mitochondrial membrane permeabilization and thus are related to different cellular response..

Review article UDC 618.19-006:612.085.1:616-097

In vivo model for research of breast cancer biomarker

Original article UDC: 618.19-006:616-037 Archive of Oncology 2002;10(3):111-14.

carcinomatous skin invasion: Does it reflect the tissue characteristics or the breast carcinoma aggressiveness

The importance of simultaneous determination of breast cancer biomarkers

It is shown that steroid hormone receptors by themselves are not sufficiently strong prognostic factors in management of breast cancer. For that reason, simultaneous consideration of different biomarkers seems to be more appropriate for clinical use, i.e. selections of patients with high/inter-mediate/low risk of disease outcome. However, the amount of tumor material available from breast carcinoma can preclude determination of estrogen- regulated biomarkers together with estrogen receptor and progesterone receptor. The aim of this study was to assess the possibility of estrogen receptor and progesterone receptor determination by a single-point instead of five-point biochemical method. Our results demonstrated that the correlation between measurements of estrogen and progesterone receptor contents obtained by the five-point and single-point assay in the total population was very high. Consequently, we could use the single-point assay instead of five-point assay for estrogen receptor and progesterone receptor determination, thus making possible determination of other molecular biomarkers from the same breast carcinoma